Worldwide nearly 200 million people are infected with HCV. Close to 2% of the U.S. population are infected with HCV, and levels in some demographic groups are much higher. In most cases, exposure to HCV results in persistent chronic infection and the majority of cases remain undetected until symptomatic. Immunosuppression, whether due to co-infection with any of several pathogens or due to treatment, enhances HCV-mediated disease progression substantially. Hence HCV infection will remain a major long-term public health burden. Despite recent evidence that failure of the immune response early in HCV infection results in persistence, little is known of the first line defense, innate immunity. There is considerable information about peripheral blood T cells in HCV infection, but little is also known of the approximately 25% intrahepatic lymphocytes (IHL) that are 'NKT' (both T & NK cell markers). A major functionally-defined NKT subset, CD1d-reactive NKT and target, CD1d, are highly conserved and have roles in initiation and control of antiviral responses, but can also cause model hepatitis. We have identified human hepatic CD 1d-reactive NKT. This proposal will determine whether human hepatic CD1d-reactive NKT in HCV infection have the functional potential to be pro-inflammatory. We will test the hypothesis that while CD1d-reactive NKT naturally respond to infected CD 1d+ liver cells during acute anti-viral responses in a novel MHC class-I like path we have defined, their chronic stimulation contributes to liver pathology. Reciprocally, we also propose that hepatocytes can damage CD1d-reactive NKT. Finally, we will also determine where the unique hepatic form of CD1d is expressed in HCV infected liver. Aim 1. Test the hypothesis that hepatic CD1d-reactive NKT may serve as pro-inflammatory and profibrotic cells in chronic HCV-mediated hepatitis and potentially contribute to liver injury. Aim 2. Determine whether HCV infection increases CD1d expression in vivo and enhances recognition of the hepatic form of CD1d by hepatic CD1d-reactive NKT in vitro. This study will provide information on whether the hepatic CD1d-NKT cell 'axis' is a suitable target for novel therapeutic interventions in HCV infection and are complementary to others of the collaborators and P.I. on acute HCV infection in chimpanzees, as well as on liver immunology and on 'NKT' cells in general.